1. Field of the Invention
The present invention relates to a DNA chip (DNA microarray) in which several thousands to not less than ten thousands kinds of different types of DNA fragments are aligned and fixed as minute spots at a high density on a base plate such as a microscopic slide glass, and a method for producing the same.
2. Description of the Related Art
The method for analyzing the genetic structure has been remarkably progressed in recent years. A large number of genetic structures represented by those of human gene have been clarified. The analysis of the genetic structure as described above uses a DNA chip (DNA microarray) in which several thousands to not less than ten thousands kinds of different types of DNA fragments are aligned and fixed as minute spots on a base plate such as a microscopic slide glass.
Those widely used as a method for forming the minute spots in the production of the DNA chip are based on a system such as the QUILL system, the pin and ring system, and the spring pin system in which a sample solution containing DNA fragments is supplied in a contact manner onto the base plate by using a so-called pin. Even when any one of the foregoing methods is adopted, it is important to suppress the dispersion of the volume and the shape of each of the minute spots to be low so that the distance between the respective minute spots is maintained to be constant.
On the other hand, in order to realize a higher density, it is also greatly expected to develop a new method in which the shape control performance is satisfactory for the minute spot, and the productivity is excellent.
When the large number of minute spots are formed on the base plate by supplying (including dripping) the sample solution, a dispenser is used, in which a large number of supply nozzles (for example, pins or spring pins) are arranged, for example, in a matrix form.
Usually, the arrangement pitch of the supply nozzles is larger than the arrangement pitch of the minute spots to be formed on the base plate. Therefore, the sample solution is supplied while deviating the supply position for the dispenser.
During this process, if any dispersion arises in the deviation width for the dispenser or in the arrangement pitch of the supply nozzles, it is feared that the dispersion is directly reflected on the arrangement state of the minute spots, and the adjoining spots are merged to one another to form one spot.
On the other hand, a procedure has been also investigated, in which the spotting is performed by using the so-called ink-jet system which is practically used for printers. However, if a supply apparatus based on the ink-jet system is used, it is feared that the adjoining spots are merged to one another to form one spot, for example, due to the influence of the so-called traveling curvature in which the direction of the discharged droplets is bent, and the unnecessary discharged droplets called satellites.
The present invention has been made taking the foregoing problems into consideration, an object of which is to provide a DNA chip which makes it possible to realize a state in which the arrangement state of a large number of minute spots to be formed on a base plate conforms to a prescribed arrangement pitch, even when any dispersion occurs in the deviation width of a dispenser or the arrangement pitch of supply nozzles, and even when any positional deviation of discharged droplets occurs due to the traveling curvature or the satellites when a supply apparatus based on the ink-jet system is used.
Another object of the present invention is to provide a method for producing a DNA chip, which makes it possible to realize a state in which the arrangement state of a large number of minute spots to be formed on a base plate conforms to a prescribed arrangement pitch, even when any dispersion occurs in the deviation width of a dispenser or the arrangement pitch of supply nozzles, and even when any positional deviation of discharged droplets occurs due to the traveling curvature or the satellites when a supply apparatus based on the ink-jet system is used, making it possible to improve the quality of the DNA chip and improve the yield.
According to the present invention, there is provided a DNA chip comprising a large number of minute spots formed by supplying sample solutions onto a base plate; wherein the base plate is provided with a positional deviation-correcting means for automatically correcting any positional deviation of the minute spot.
Accordingly, when the sample solution is supplied onto the base plate, even if the supply position is deviated from a prescribed position, then the minute spot to be formed by supplying the sample solution is moved to the prescribed position by the aid of the positional deviation-correcting means. Thus, the positional deviation is corrected.
As described above, according to the DNA chip concerning the present invention, it is possible to realize a state in which the arrangement state of the large number of minute spots to be formed on the base plate conforms to a prescribed arrangement pitch, even when any dispersion occurs in the deviation width of a dispenser or the arrangement pitch of supply nozzles, and even when any positional deviation of discharged droplets occurs due to the traveling curvature or the satellites when a supply apparatus based on the ink-jet system is used.
According to another aspect of the present invention, there is provided a method for producing a DNA chip by supplying a large number of sample solutions onto a base plate; comprising the step of using, as the base plate, a base plate provided with a positional deviation-correcting means for automatically correcting any positional deviation of the minute spot to produce the DNA chip.
Accordingly, it is possible to realize a state in which the arrangement state of the large number of minute spots to be formed on the base plate conforms to a prescribed arrangement pitch, even when any dispersion occurs in the deviation width of a dispenser or the arrangement pitch of supply nozzles, and even when any positional deviation of discharged droplets occurs due to the traveling curvature or the satellites when a supply apparatus based on the ink-jet system is used, making it possible to improve the quality of the DNA chip and improve the yield.
It is preferable that the sample solution is supplied by using a supply apparatus based on the ink-jet system. In this case, it is preferable that the supply apparatus is a dispenser comprising a plurality of arranged micropipettes each including a pouring port for pouring the sample solution from the outside, a cavity for pouring and charging the sample solution thereinto, and a discharge port for discharging the sample solution, formed on at least one or more substrates, the micropipette further including a piezoelectric/electrostrictive element disposed on at least one wall surface of the substrate which forms the cavity so that the sample solution is movable in the cavity, and mutually different types of the sample solutions being discharged from the discharge ports of the respective micropipettes. Further, it is more preferable that the sample solution is moved in a laminar flow.
When the ink-jet system is used, then the minute spot can be formed at a high speed, and it is possible to freely set the speed and the liquid amount of the discharged droplets. Therefore, the following advantages are obtained. That is, it is possible to correctly form the minute spot with the prescribed liquid amount and/or with the shape. The dispersion between the respective minute spots is decreased as compared with a system in which the operation is performed with a pin or a spring pin.
Unlike the pin system, the minute spot is formed in a non-contact manner in the ink-jet system. Therefore, there is neither physical interference nor contact with respect to the positional deviation-correcting means. Thus, the ink-jet system can be preferably used.
Concerning the degree of freedom of the design, for example, of the spot amount and the discharge speed, possessed by the ink-jet system, another advantage is obtained such that it is easy to effect the matching with the positional deviation-correcting means. That is, the following advantage is obtained. When the correction is to be made to a great extent due to a large positional deviation amount, the contact with the positional deviation-correcting means may be facilitated, for example, by increasing the discharge amount and the discharge speed to enlarge the spread of the spot on the base plate. Thus, it is possible to perform the correction of the positional deviation in a reliable manner.
It is also preferable that the positional deviation-correcting means is a projection formed at a position at which the minute spot is to be formed on the base plate, or the positional deviation-correcting means is constructed by a hydrophilic zone formed at a position at which the minute spot is to be formed, and a water-repellent zone formed at the other portions on the base plate.
It is also preferable that the positional deviation-correcting means is a recess formed at a position at which the minute spot is to be formed on the base plate, or the positional deviation-correcting means is constructed by providing different surface state for a portion at which the minute spot is to be formed and the other portions on the base plate.
It is also preferable that the positional deviation-correcting means includes an electric field-generating means for providing a charged state of a portion at which the minute spot is to be formed, the charged state being opposite to that of the sample solution on the base plate.
For example, the electric field-generating means is operated as follows. That is, when the sample solution is negatively charged (minus charge), if the portion, at which the minute spot is to be formed, is allowed to have the charged state opposite to that of the sample solution, i.e., the positive charged state (state of plus charge), then the spotting can be reliably performed at the prescribed position, which is preferred. When the sample solution is in the state of plus charge, the portion, at which the minute spot is to be formed, may be in the state of minus charge.
Further, when the ink-jet system is used as the system for supplying the sample solution, the minute spot can be formed in a non-contact manner. Therefore, the discharge direction of droplets is aligned with the direction of the electric field. Further, the correction is easily made for the dripping position by the aid of the electric field. Therefore, this system can be preferably used.
When the sample solution is a solution containing the DNA fragment, the following procedure is preferred in order to obtain a more effective positional deviation-correcting effect by the electric field. That is, a functional group for adding the charge is added to the DNA fragment, or the DNA fragment is dispersed in a solution having charge.